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Characterisation and prognosis of undiagnosed chronic obstructive pulmonary disease patients at their first hospitalisation

  • Balcells Vilarnau, Eva, 1967-
  • Gimeno Santos, Elena, 1980-
  • De Batlle, Jordi
  • Ramon, Maria Antonia
  • Rodríguez, Esther
  • Benet, Marta
  • Ferrer, Jaume
  • Farrero, Eva
  • Ferrer, Antoni-Lluc, 1942-
  • Guerra, Stefano
  • Ferrer, Jaume
  • Sauleda Roig, Jaume
  • Barberà, Joan Albert
  • Agustí, Alvar
  • Rodriguez, Robert, 1968-
  • Gea Guiral, Joaquim
  • Antó i Boqué, Josep Maria
  • García Aymerich, Judith
Background. Under-diagnosis of COPD is an important unmet medical need. We investigated the characteristics and prognosis of hospitalised patients with undiagnosed COPD./nMethods. The PAC-COPD cohort included 342 COPD patients hospitalised for the first time for an exacerbation of COPD (2004–2006). Patients were extensively characterised using sociodemographic, clinical and functional variables, and the cohort was followed-up through 2008. We defined “undiagnosed COPD” by the absence of any self-reported respiratory disease and regular use of any pharmacological respiratory treatment./nResults. Undiagnosed COPD was present in 34% of patients. They were younger (mean age 66 vs. 68 years, p = 0.03), reported fewer symptoms (mMRC dyspnoea score, 2.1 vs. 2.6, p < 0.01), and had a better health status (SGRQ total score, 29 vs. 40, p < 0.01), milder airflow limitation (FEV1% ref., 59% vs. 49%, p < 0.01), and fewer comorbidities (two or more, 40% vs. 56%, p < 0.01) when compared with patients with an established COPD diagnosis. Three months after hospital discharge, 16% of the undiagnosed COPD patients had stopped smoking (vs. 5%, p = 0.019). During follow-up, annual hospitalisation rates were lower in undiagnosed COPD patients (0.14 vs. 0.25, p < 0.01); however, this difference disappeared after adjustment for severity. Mortality was similar in both groups./nConclusions. Undiagnosed COPD patients have less severe disease and lower risk of re-hospitalisation when compared with hospitalised patients with known COPD., The PAC-COPD Study is funded by grants from Fondo de Investigación Sanitaria (FIS PI020541), Ministry of Health, Spain; Agència d’Avaluació de Tecnologia i Recerca Mèdiques (AATRM 035/20/02), Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery (SEPAR 2002/137); Catalan Foundation of Pneumology (FUCAP 2003 Beca Marià Ravà); Red RESPIRA (RTIC C03/11); Red RCESP (RTIC C03/09); Fondo de Investigación Sanitaria (PI052486); Fondo de Investigación Sanitaria (PI052302); Fondo de Investigación Sanitaria (PI060684); Fundació La Marató de TV3 (num. 041110); and Novartis Farmacèutica, Spain. CIBERESP and CIBERES are funded by the Instituto de Salud Carlos III, Ministry of Health, Spain.

Her9 represses neurogenic fate downstream of Tbx1 and retinoic acid signaling in the inner ear

  • Radosevic, Marija, 1978-
  • Robert Moreno, Alexandre
  • Coolen, Marion
  • Bally-Cuif, Laure
  • Alsina i Español, Berta
Proper spatial control of neurogenesis in the inner ear ensures the precise innervation of mechanotransducing cells and the propagation of auditory and equilibrium stimuli to the brain. Members of the Hairy and enhancer of split (Hes) gene family regulate neurogenesis by inhibiting neuronal differentiation and maintaining neural stem cell pools in non-neurogenic zones. Remarkably, their role in the spatial control of neurogenesis in the ear is unknown. In this study, we identify her9, a zebrafish ortholog of Hes1, as a key gene in regulating otic neurogenesis through the definition of the posterolateral non-neurogenic field. First, her9 emerges as a novel otic patterning gene that represses proneural function and regulates the extent of the neurogenic domain. Second, we place Her9 downstream of Tbx1, linking these two families of transcription factors for the first time in the inner ear and suggesting that the reported role of Tbx1 in repressing neurogenesis is in part mediated by the bHLH transcriptional repressor Her9. Third, we have identified retinoic acid (RA) signaling as the upstream patterning signal of otic posterolateral genes such as tbx1 and her9. Finally, we show that at the level of the cranial otic field, opposing RA and Hedgehog signaling position the boundary between the neurogenic and non-neurogenic compartments. These findings permit modeling of the complex genetic cascade that underlies neural patterning of the otic vesicle., M.R. was supported by an FPI fellowship from MICIIN and A.R.-M. from a JdC postdoctoral contract from MICINN. Grant support was from BFU2008-00714 from MICINN

Jagged 1 regulates the restriction of Sox2 expression in the developing chicken inner ear: a mechanism for sensory organ specification

  • Neves, Joana
  • Parada, Carolina
  • Chamizo, Mireia
  • Giráldez, Fernando
Hair cells of the inner ear sensory organs originate from progenitor cells located at specific domains of the otic vesicle: the prosensory patches. Notch signalling is necessary for sensory development and loss of function of the Notch ligand jagged 1 (Jag1, also known as serrate 1) results in impaired sensory organs. However, the underlying mechanism of Notch function is unknown. Our results show that in the chicken otic vesicle, the Sox2 expression domain initially contains the nascent patches of Jag1 expression but, later on, Sox2 is only maintained in the Jag1-positive domains. Ectopic human JAG1 (hJag1) is able to induce Sox2 expression and enlarged sensory organs. The competence to respond to hJag1, however, is confined to the regions that expressed Sox2 early in development, suggesting that hJag1 maintains Sox2 expression rather than inducing it de novo. The effect is non-cell-autonomous and requires Notch signalling. hJag1 activates Notch, induces Hes/Hey genes and endogenous Jag1 in a non-cell-autonomous manner, which is consistent with lateral induction. The effects of hJag1 are mimicked by Jag2 but not by Dl1. Sox2 is sufficient to activate the Atoh1 enhancer and to ectopically induce sensory cell fate outside neurosensory-competent domains. We suggest that the prosensory function of Jag1 resides in its ability to generate discrete domains of Notch activity that maintain Sox2 expression within restricted areas of an extended neurosensory-competent domain. This provides a mechanism to couple patterning and cell fate specification during the development of sensory organs.

ADF/cofilin regulates secretory cargo sorting at the TGN via the Ca2+ ATPase SPCA1

  • Blume, Julia von
  • Alleaume, Anne-Marie
  • Cantero Recasens, Gerard, 1984-
  • Curwin, Amy
  • Carreras Sureda, Amado, 1986-
  • Zimmermann, Timo
  • Galen, Josse van
  • Wakana, Yuichi
  • Valverde, M. A. (Miguel Ángel), 1963-
  • Malhotra, Vivek
Actin-severing proteins ADF/cofilin are required for the sorting of secretory cargo at the trans-Golgi network (TGN) in mammalian cells. How do these cytoplasmic proteins interact with the cargoes in the lumen of the TGN? Put simply, how are these two sets of proteins connected across the TGN membrane? Mass spectrometry of cofilin1 immunoprecipitated from HeLa cells revealed the presence of actin and the Ca(2+) ATPase SPCA1. Moreover, cofilin1 was localized to the TGN and bound to SPCA1 via dynamic actin. SPCA1 knockdown, like ADF/cofilin1 knockdown, inhibited Ca(2+) uptake into the TGN and caused missorting of secretory cargo. These defects were rescued by the overexpression of the TGN-localized SPCA1. We propose that ADF/cofilin-dependent severing of actin filaments exposes and promotes the activation of SPCA1, which pumps Ca(2+) into the lumen of the TGN for the sorting of the class of secretory cargo that binds Ca(2+).

Control of Ubp3 ubiquitin protease activity by the Hog1 SAPK modulates transcription upon osmostress

  • Solé, Carme
  • Nadal Ribelles, Mariona, 1984-
  • Kraft, Claudine
  • Peter, Matthias
  • Posas Garriga, Francesc
  • Nadal Clanchet, Eulàlia de
Protein ubiquitylation is a key process in the regulation of many cellular processes. The balance between the activity of ubiquitin ligases and that of proteases controls the level of ubiquitylation. In response to extracellular stimuli, stress-activated protein kinases (SAPK) modulate gene expression to maximize cell survival. In yeast, the Hog1 SAPK has a key role in reprogramming the gene expression pattern required for cell survival upon osmostress. Here, we show that the Ubp3 ubiquitin protease is a target for the Hog1 SAPK to modulate gene expression. ubp3 mutant cells are defective in expression of osmoresponsive genes. Hog1 interacts with and phosphorylates Ubp3 at serine 695, which is essential to determine the extent of transcriptional activation in response to osmostress. Furthermore, Ubp3 is recruited to osmoresponsive genes to modulate transcriptional initiation as well as elongation. Therefore, Ubp3 activity responds to external stimuli and is required for transcriptional activation upon osmostress., MN is the recipient of an FIS (Spanish Government) fellowship and FP is the recipient of an ICREA Acadèmia (Generalitat de Catalunya). This work was supported by Fundación Marcelino Botín (FMB) and grants from the Spanish Ministry of Science and Innovation (BFU2008-00530 to EN and BIO2009-07762 to FP) and the FP7 (UNICELLSYS) framework programme.

Sir2 histone deacetylase prevents programmed cell death caused by sustained activation of the Hog1 stress-activated protein kinase

  • Vendrell Arasa, Alexandre
  • Martínez Pastor, Mar
  • González Novo, Alberto
  • Pascual Ahuir, Amparo
  • Sinclair, David A.
  • Proft, Markus
  • Posas Garriga, Francesc
Exposure of yeast to high osmolarity induces a transient activation of the Hog1 stress-activated protein kinase (SAPK), which is required for cell survival under these conditions. However, sustained activation of the SAPK results in a severe growth defect. We found that prolonged SAPK activation leads to cell death, which is not observed in nma111 cells, by causing accumulation of reactive oxygen species (ROS). Mutations of the SCF(CDC4) ubiquitin ligase complex suppress cell death by preventing the degradation of Msn2 and Msn4 transcription factors. Accumulation of Msn2 and Msn4 leads to the induction of PNC1, which is an activator of the Sir2 histone acetylase. Sir2 is involved in protection against Hog1-induced cell death and can suppress Hog1-induced ROS accumulation. Therefore, cell death seems to be dictated by the balance of ROS induced by Hog1 and the protective effect of Sir2., This work was supported by grants from the Ministerio de Ciència y Innovación (BIO2009-07762) and Consolider Ingenio 2010 programme (grant CSD2007-0015), UNICELLSYS from FP7, as well as supported byFundación Marcelino Botín. F.P. is the recipient of the Institució Catalana de Recerca i Estudis Avançats Acadèmia (Generalitat de Catalunya). D.A.S. is supported by grants from the National Institute on Aging National Institutes of Health, the Ellison Medical Foundation and the Glenn Foundation for Medical Research.

Transcriptomic analysis of a psammophyte food crop, sand rice (Agriophyllum squarrosum) and identification of candidate genes essential for sand dune adaptation

  • Zhao, Pengshan
  • Capella Gutiérrez, Salvador Jesús, 1985-
  • Shi, Yong
  • Zhao, Xin
  • Chen, Guoxiong
  • Gabaldón Estevan, Juan Antonio, 1973-
  • Ma, Xiao-Fei
Background. Sand rice (Agriophyllum squarrosum) is an annual desert plant adapted to mobile sand dunes in arid and semi-arid regions of Central Asia. The sand rice seeds have excellent nutrition value and have been historically consumed by local populations in the desert regions of northwest China. Sand rice is a potential food crop resilient to ongoing climate change; however, partly due to the scarcity of genetic information, this species has undergone only little agronomic modifications through classical breeding during recent years./nResults. We generated a deep transcriptomic sequencing of sand rice, which uncovers 67,741 unigenes. Phylogenetic analysis based on 221 single-copy genes showed close relationship between sand rice and the recently domesticated crop sugar beet. Transcriptomic comparisons also showed a high level of global sequence conservation between these two species. Conservation of sand rice and sugar beet orthologs assigned to response to salt stress gene ontology term suggests that sand rice is also a potential salt tolerant plant. Furthermore, sand rice is far more tolerant to high temperature. A set of genes likely relevant for resistance to heat stress, was functionally annotated according to expression levels, sequence annotation, and comparisons corresponding transcriptome profiling results in Arabidopsis./nConclusions. The present work provides abundant genomic information for functional dissection of the important traits in sand rice. Future screening the genetic variation among different ecotypes and constructing a draft genome sequence will further facilitate agronomic trait improvement and final domestication of sand rice., TG group research is funded in part by a grant from the Spanish ministry of Economy and Competitiveness (BIO2012-37161), a Grant from the Qatar National Research Fund grant (NPRP 5-298-3-086), and a grant from the European Research Council under the European Union's Seventh Framework/nProgramme (FP/2007-2013)/ERC (Grant Agreement n. ERC-2012-StG-310325)

Cooperation between dE2F1 and Yki/Sd defines a distinct transcriptional program necessary to bypass cell cycle exit

  • Nicolay, Brandon N.
  • Bayarmagnai, Battuya
  • Islam, Abul, 1978-
  • López Bigas, Núria
  • Frolov, Maxim V.
The Hippo signaling pathway regulates organ size homeostasis, while its inactivation leads to severe hyperplasia in flies and mammals. The transcriptional coactivator Yorkie (Yki) mediates transcriptional output of the Hippo signaling. Yki lacks a DNA-binding domain and is recruited to its target promoters as a complex with DNA-binding proteins such as Scalloped (Sd). In spite of recent progress, an open question in the field is the mechanism through which the Yki/Sd transcriptional signature is defined. Here, we report that Yki/Sd synergizes with and requires the transcription factor dE2F1 to induce a specific transcriptional program necessary to bypass the cell cycle exit. We show that Yki/Sd and dE2F1 bind directly to the promoters of the Yki/Sd-dE2F1 shared target genes and activate their expression in a strong cooperative manner. Consistently, RBF, a negative regulator of dE2F1, negates this synergy and limits the overall level of expression of the Yki/Sd-dE2F1 target genes. Significantly, dE2F1 is needed for Yki/Sd-dependent full activation of these target genes, and a de2f1 mutation strongly blocks yki-induced proliferation in vivo. Thus, the Yki transcriptional program is determined through functional interactions with other transcription factors directly at target promoters. We suggest that such functional interactions would influence Yki activity and help diversify the transcriptional output of the Hippo pathway.

mir-11 limits the proapoptotic function of its host gene, dE2f1

  • Truscott, Mary
  • Islam, Abul, 1978-
  • López Bigas, Núria
  • Frolov, Maxim V.
The E2F family of transcription factors regulates the expression of both genes associated with cell proliferation and genes that regulate cell death. The net outcome is dependent on cellular context and tissue environment. The mir-11 gene is located in the last intron of the Drosophila E2F1 homolog gene dE2f1, and its expression parallels that of dE2f1. Here, we investigated the role of miR-11 and found that miR-11 specifically modulated the proapoptotic function of its host gene, dE2f1. A mir-11 mutant was highly sensitive to dE2F1-dependent, DNA damage-induced apoptosis. Consistently, coexpression of miR-11 in transgenic animals suppressed dE2F1-induced apoptosis in multiple tissues, while exerting no effect on dE2F1-driven cell proliferation. Importantly, miR-11 repressed the expression of the proapoptotic genes reaper (rpr) and head involution defective (hid), which are directly regulated by dE2F1 upon DNA damage. In addition to rpr and hid, we identified a novel set of cell death genes that was also directly regulated by dE2F1 and miR-11. Thus, our data support a model in which the coexpression of miR-11 limits the proapoptotic function of its host gene, dE2f1, upon DNA damage by directly modulating a dE2F1-dependent apoptotic transcriptional program.

Databases and resources for human small non-coding RNAs

  • Agirre Ortiz de Guzmán, Eneritz, 1983-
  • Eyras Jiménez, Eduardo
Recent advances in high-throughput sequencing have facilitated the genome-wide studies of small non-coding RNAs (sRNAs). Numerous studies have highlighted the role of various classes of sRNAs at different levels of gene regulation and disease. The fast growth of sequence data and the diversity of sRNA species have prompted the need to organise them in annotation databases. There are currently several databases that collect sRNA data. Various tools are provided for access, with special emphasis on the well-characterised family of micro-RNAs. The striking heterogeneity of the new classes of sRNAs and the lack of sufficient functional annotation, however, make integration of these datasets a difficult task. This review describes the currently available databases for human sRNAs that are accessible via the internet, and some of the large datasets for human sRNAs from high-throughput sequencing experiments that are so far only available as supplementary data in publications. Some of the main issues related to the integration and annotation of sRNA datasets are also discussed.

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